胚胎期—新生期缺碘及成年期缺碘对中枢神经系统影响的实验研究INFLUENCES OF FETO-NEONATAL AND ADULTHOOD IODINE DEPLETION ON THE CENTRAL NERVOUS SYSTEM IN RATS

地方克汀病是世界上分布广泛、危害严重的地方病之一。至今,其病因和发病机制仍不十分清楚。根据大量流行病学和临床研究的资料,多数学者认为地方克汀病是由于胚胎期与新生儿期缺碘和甲状腺激素不足,造成中枢神经系统和骨骼系统等的不可逆性损伤所致。但在实验动物中,仅用单纯缺碘的方法,仍未能成功地复制出地方克汀病模型。本实验自妊娠中期直至哺乳期给母鼠饲以人工配制的低碘饮食,使仔鼠胚胎后期及哺乳期缺碘,采用运动防御条件反射,脑电图和脑的形态改变为指标,检查仔鼠脑功能和形态的变化,来探讨胚胎期和新生儿期缺碘在地方克汀病发病机制中的作用。本实验还以同样的方法检查了成年大鼠的脑功能和形态变化,观察成年期The etiology and pathogenesis of endemic cretinism are still debatable prob- lems. It has been insisted by most investigators that this disease is due to hypo- thyroidism caused by prenatal and neonatal iodine-deficiency on the basis of epidemiological and clinical data. However, there is no successful report of produc tion of an animal model of cretinism with single iodine depletion up to date. Many investigators have studied the effects of hypothyroidism caused by surgical thyroidectomy, ~(131)I radiothyroidectomy and chronic administration of propylthiouracil at birth on the development of the central nervous system in rats and observed significant abnormalities. But the methods used to induce hypo- thyroidism did not identify with the natural cause of endemic cretinism. In order to study the effects of iodine-deficiency and hypothyroidism in the fetal and neonatal periods on the development of the brain, the offspring of mother wistar rats maintained on a low-iodine diet since the middle gestation to the lactation were studied with motor defence conditional reflex test, electroencephalography, and morphologic examination of the brain. In addition, iodine-deficient adult rats were also examined with similar methods to study the effects of iodine-defi- ciency on the mature brain. To verify the correlation between the changes of the brain and the condition of the thyroid under iodine-deficiency, morphologic changes of the thyroid and serum T_4 value were studied. Experiment I. Feto-neonatal iodinedeficiency 18 offsprings from iodine-deficient dams fed a low-iodine diet (LID) since about the 10th day of gestation to the lactation and 22 offsprings from control dams fed a sufficient iodine supplement diet (SISD) were studied. The iodine-deficient pups 14 days old showed morphologic abnormalities: increased density of neurons in the cerebral cortex, higher percentage of undif- ferentiated neuroblasts, shorter and less frequently branched dendrites of pyrami- dal cells, retardation of disappearance of the external granular layer of the cere- bellar cortex, less frequently branched dendrites of Purkinje's cells, and reduced myelination of nervous fibers of the cerebrum and cerebellum. No significant ab- normality was seen on EEG. The thyroid enlarged markedly and exhibited a typical pattern of hyperplastic goiter. The Serum T_4 was within the normal range. The pups 30--40 days old showed a prolonged latent period of the escape response to the unconditional electric stimulus. EEG showed no odvious abnor- mality. The brain showed only increased density of neurons and higher pereen- tage of undifferentiated neuroblasts in the cerebral cortex. Other morphologic changes seen at the 14 days of age were not found. The average thyroid weight was 2.5 times that of the control pups. The Serum T_4 decreased significantly. The above data indicate that fetal and neonatal iodine-deficiency may lead to a retardation of the development of the brain. It is worthy to state that among 18 iodine-deficient infant rats, there was one showing abnormal changes probably significant of cretisanism. There was a marked impairment of growth. The hair coat was sparse and dry. The animal appeared listless and relatively immobil with an unbalanced gait. No escape response to the electric stimulus occured in most cases, so that the conditional reflex was unable to be established at all. The cerebral cortex also showed markedly increased density of neurons and higher percentage of undifferentiated neuroblasts. Weil's specimens displayed poorer myelination. The thyroid exhibited hyperplastic goiter. The Serum T_4 decreased markedly. The faet that only one of 18 feto-neonatal iodine-deficient rats was induced to cretinism suggests a possible role played by some individual factors in the pathogenesis of cretinism. Experiment 11. Adulthood iodine-deficiency 54 adult rats were divided random into two groups: (1) iodine-deficiency group (n=30) fed the LID. (2) control group(n=24) fed the SISD. A part of rats of both groups respectively were examined at the 17th, 35th and 97th day of the experiment for the serum T_4 concentration and the morphology of the thyroid. By the 97th day of the experiment, the surviving animals of the iodine-deficiency group were divided again into 3 subgroups, each of which was given one of the following regimens respectively for a further period of 7 to 20 days. (a) LID. (b) LID with thyroxine, (c) SISD. The animals were studied for the conditional reflex, EEG, morphologic changes of the brain and thyroid, and serum T_4 concentration at the end of the experiment. The animals fed the LID persistently showed marked impairment of the ability to establish stable conditonal reflex, decreased speed of the reaction to the electr stimulus and conditional signal, and declined amplitude of the waves on EEG. No degenerative changes were seen in the brain. The thyroid showed a picture of hyperplastic goiter. The serum T_4 concentration lowered markedly. The above findings suggest that iodine-deficiency and hypothyroidism may also affect the function of the maturely developed brain. However, the impairment of the func- tion of the mature brain caused by iodine-deficiency and hypothroidism in adulthood might be temporary and reversible since they were prevented with thyroxine and sufficient iodine supplement.